Opioid modulation of neural encoding of motivation and reward

描述（由申请人提供）：我们的长期目标是了解神经奖励回路在正常消费期间以及在包括暴食的病理中对控制食物摄入的贡献。我们特别感兴趣的是奖励回路中的阿片信号，特别是在核壳（sNAc）中，介导暴食样食物摄入。sNAcc中μ阿片受体（MOR）的刺激诱导贪婪进食，并且在饮食诱导的暴食大鼠模型中改变sNAcc阿片受体和配体表达。然而，sNAcc莫尔刺激引起食欲亢进的机制，以及饮食诱导的该回路变化如何导致暴食行为，仍然知之甚少。在以前的研究中，我们表征了sNAcc神经元中的两种放电模式，我们假设它们在处理味觉享乐和控制食欲觅食行为中发挥重要而独特的作用。我们的数据表明，第一个这些发射模式编码适口性，而第二个用于通过去抑制机制允许门的觅食行为（和随后的消费）。在本建议中，我们将测试的假设，sNAcc莫尔刺激对这些放电模式的不同影响，以增加适口性诱导的食欲过盛和食物寻求食欲行为，通过信号在隔离的解剖途径。我们进一步假设，饮食诱导的暴饮暴食是通过神经通路中介导食欲寻找的阿片类信号的敏化而产生的，而不是通过处理适口性的通路的变化。为了解决这些假设，我们将使用体内电生理学和药理学方法的组合来表征sNAcc莫尔操作对sNAcc的传出靶点中的放电的影响。我们将研究sNAcc和目标区域之间的相互作用，同时使用电极阵列记录和互相关技术来表征这些区域之间的功能连接。最后，我们将描述在饮食诱导的暴食大鼠模型中发生在该回路中的电生理和药理学变化。我们预期这些实验将为sNAcc莫尔刺激和饮食诱导的暴饮暴食引起的摄食过多的潜在机制提供重要的见解。这些实验将导致对强迫性食物摄入的神经回路机制有更深入的了解，因此在开发新的治疗饮食失调（如神经性贪食症）的干预措施方面具有高度相关性。

DESCRIPTION (provided by applicant): Our long-term goal is to understand the contribution of neural reward circuits to control of food intake during normal consumption as well as in pathologies that incorporate binge eating. We are specifically interested in how opioid signaling within reward circuits, particularly in the shell of the nucleus accumbens (sNAcc), mediates binge-like food intake. Stimulation of mu opioid receptors (MORs) in the sNAcc induces voracious feeding and sNAcc opioid receptor and ligand expression is altered in rat models of diet-induced binge eating. However, the mechanisms through which sNAcc MOR stimulation causes hyperphagia, and how diet-induced changes in this circuit contribute to binge eating behavior, remain poorly understood. In previous studies, we characterized two firing patterns in sNAcc neurons that we hypothesize play important and distinct roles in processing of taste hedonics and controlling appetitive food-seeking behavior. Our data suggests that the first of these firing patterns encodes palatability, while the second serves to permissively gate food-seeking behavior (and subsequent consumption) through a disinhibition mechanism. In the present proposal, we will test the hypothesis that distinct effects of sNAcc MOR stimulation on these firing patterns act to increase palatability-induced hyperphagia and food-seeking appetitive behaviors through signaling in segregated anatomical pathways. We further hypothesize that diet-induced binge eating arises specifically through sensitization of opioid signaling in the neural pathway mediating appetitive food-seeking, rather than through changes in pathways processing palatability. To address these hypotheses, we will use a combination of in vivo electrophysiological and pharmacological approaches to characterize the effects of sNAcc MOR manipulations on firing in efferent targets of the sNAcc. We will investigate interactions between the sNAcc and target regions using simultaneous electrode array recordings and cross-correlation techniques to characterize functional connectivity between these regions. Finally, we will characterize electrophysiological and pharmacological changes occurring in this circuit in a rat model of diet-induced binge eating. We anticipate that these experiments will provide important insights into the mechanisms underlying hyperphagia caused by sNAcc MOR stimulation and diet-induced binge eating. These experiments will lead to greater understanding of neural-circuit mechanisms underlying compulsive food intake, and are thus highly relevant in developing novel therapeutic interventions for eating disorders such as bulimia nervosa.